Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1c(C2=NN(Cc3cccc(F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Fluorobenzyl bromide (8 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: C(=O)([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)OC.[CH3:12][Si:13]([CH3:16])([CH3:15])Br>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.S1(CCCC1)(=O)=O>[O:4]([Si:13]([CH3:16])([CH3:15])[CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)Br
Reactant: COC(=O)Oc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S1(=O)CCCC1
Product: C[Si](C)(C)Oc1ccccc1
Temperature: 120 °C
Yield: 65 %

Procedure:
A mixture of 3.8 g (0.025 g mole) of methyl phenyl carbonate, 3.83 g (0.025 g mole) of trimethylbromosilane, and 0.09 g of tetra-n-butyl phosphonium bromide in 15 ml of sulfolane was heated at 120° C. in a reaction flask equipped with a reflux condenser. After 16 hours of heating, the reflux condenser was replaced by a distillation head and 2.7 g (65 percent yield) of phenoxytrimethylsilane was distilled at reduced pressure from the reaction mixture at a head temperature of 71° C.-72° C./18 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:11]=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[O:3]1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:28]1[CH2:27][CH:26]1[CH2:24][O:22][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[CH:11][C:2]([CH3:23])([CH3:1])[O:3]2)=[CH:8][CH:7]=1
Reactant: ClCC1CO1
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Yield: 86 %

Procedure:
2,2-Dimethyl-4-(1-naphthyl)-2H-chromen-7-ol (7.92 g, 0.026 moles) and epichlorohydrin (28,5 ml) were dissolved in acetone (50 ml). Potassium carbonate (6.3 g), was added and the mixture refluxed for 6 hours, allowed to cool and filtered. The acetone was removed in vacuo and the residue dissolved in ether, washed with water and dried. Removal of solvent gave the title product as an orange oil (8.1 g, 86%) which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.ON1C2C=CC=CC=2N=N1.[C:23](O)(=[O:32])[C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:25][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:32]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CC(N)CCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Temperature: -5 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a cooled (-5° C.) solution of 32 g of the above enriched amine, 33 g of 1-hydroxybenzotriazole and 31.22 g of (R)-mandelic acid in 350 mL of dimethylformamide, was added a solution of 44.26 g of 1,3-dicyclohexylcarbodiimide in 150 mL of dimethylformamide and the mixture was stirred at -5° C. for 18 hours. After the precipitated dicyclohexylurea was removed by filtration, the filtrate was evaporated and the residue dispersed in 300 mL of cold 2N sodium hydroxide. The resulting solids were removed by filtration, washed with dilute sodium hydroxide solution and with water and then dissolved in 500 mL of 2N hydrochloric acid. The acidic solution was extracted with dichloromethane (3×150 mL) to remove neutral impurities, then was basified with 10N sodium hydroxide and extracted with dichloromethane (6×300 mL). The dried extracts were evaporated to give 55 g of residual solid. Crystallization of the product from ethanol gave 25.6 g of [R-(R*,R)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 141°-143° C. An additional 1.3 g of product, mp 141°-143° C., was obtained from the mother liquors.
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21]([OH:23])([CH3:4])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOCC
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a 3.0 M solution of methylmagnesium bromide in Et2O (0.98 mL, 2.92 mmol), at 0° C., was added a solution of 3-oxoazetidine-1-carboxylic acid benzyl ester (0.5 g, 2.44 mmol) in anhydrous THF (5 mL) dropwise over 5 min under argon. The reaction mixture was stirred for 18 h at room temperature, and then quenched by addition of a saturated aqueous solution of NH4Cl (2.5 mL) and water (5 mL). The aqueous phase was extracted with EtOAc (10 mL). The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give 3-Hydroxy-3-methylazetidine-1-carboxylic acid benzyl ester as a colourless oil (0.54 g, 99%). LCMS (Method A): RT=3.60 min, [M+H]+ 221.9
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]([C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])=[O:20])[C:8]([N:10]([CH2:17][CH3:18])[C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C([NH:40][C:41]1C=NC=[CH:45][CH:46]=1)(C)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH:7]([C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])=[O:20])[C:8]([N:10]([CH:11]([CH3:12])[CH3:16])[C:17]2[CH:18]=[N:40][CH:41]=[CH:46][CH:45]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)C(Cc1ccc(Cl)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: CC(C)Nc1cccnc1
Agent: Cl
Solvent: CCO
Product: CC(C)N(C(=O)C(Cc1ccc(Cl)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1cccnc1
Yield: 32.2 %

Procedure:
In the same manner as in Example 13, the object compound was obtained using the compound (418 mg) obtained in Example 267 (1) and 3-(isopropylamino)pyridine (163 mg). This was dissolved in ethanol, 1 mol/L hydrochloric acid was added, and the mixture was concentrated under reduced pressure to give the title compound (74 mg) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:11]2[N:12]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CO.O>[NH:15]([C:13]1[S:14][C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[C:11]=2[N:12]=1)[C:16]([NH2:18])=[NH:17]
Reactant: CCOC(=O)C1CCCc2sc(NC(=N)N)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(N)Nc1nc2c(s1)CCCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A suspension of 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester (5 mmol) and sodium hydroxide (20 mmol) in methanol/water (4:1, 10 ml) is stirred overnight at room temperature. The pH is set at 5 by adding 25% hydrochloric acid and the precipitated product is filtered off. In this way the title compound is obtained (671 mg) in a yield of 56%: tR 0.64 min (LC-1); ESI-MS (+/−): m/z 241.49 [M+H]+/239.37 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[C:68]([CH:71]=[CH:72][CH:73]=1)[CH2:69][OH:70]>C(Cl)Cl>[OH:70][CH2:69][C:68]1[CH:67]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])[CH:73]=[CH:72][CH:71]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccc(CO)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(CO)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 104 mg, 0.27 mmol) was added followed by the addition of DIPEA (80 uL,) and 3-amino benzyl alcohol (Aldrich, 80 uL). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified reverse phase HPLC (24 g column, eluent, ACN/water, 20-90) to give a white solid. 40 mg.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br-].[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O.O>[CH2:1]([N:8]([CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[N:14]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCc2nc(-c3ccc(-c4ccccc4)cc3)c[nH]2)cc1
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccccc1)Cc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reaction time: 3 h
Yield: 13 %

Procedure:
N-benzyl(4-(1,1′-biphenyl)-4-yl-1H-imidazol-2-yl)methanamine (1 g; 0.0024 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 15 ml dimethylformamide. Potassium carbonate (1 g; 0.0073 mol) was added at about 23° C. and then hexane bromide (0.34 ml; 0.0024 mol) was added quite slowly. The reaction mixture was brought around the temperature of about 70° C. for about 3 hours before being poured in icy water. The mixture was extracted with ethyl acetate and the organic phase washed with water. After drying over magnesium sulfate, the solvents were concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/7-3), a light yellow solid was obtained in the form of a glue (yield of 13%). Free base. Melting point: 120-122° C. MH+=424.3.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([NH:14][C:15]([NH2:17])=[NH:16])(=[O:13])[CH3:12]>CN(C=O)C.CCOC(C)=O>[C:5]1([C:3]2[N:16]=[C:15]([NH:14][C:11](=[O:13])[CH3:12])[NH:17][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)NC(=N)N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.0 g (10 mmol) of 2-bromoacetophenone in DMF (30 mL) was added 3.0 g (29 mmol) 1-acetylguanidine in one portion, the reaction mixture was stirred at rt for 2 days. The reaction mixture was diluted with EtOAc (250 mL) and washed with saturated NH4Cl aq. solution (50 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by a flash column chromatography eluting with EtOAc to give N-(4-phenyl-1H-imidazol-2-yl)-acetamide. (0.5 g, 24%). LCMS: 203 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CCO)c1ccccc1
Product: CCN(CCOC(C)=O)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 49.6 g (300 mmol) of 15 and 50 ml of acetic acid anhydride in a 250 ml-flask, equipped with a CaCl2-tube is stirred overnight at 60° C. Then, the volatile compounds are evaporated and the crude product is distilled under vacuüm.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]1([N:16]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2B2OC(C)(C)C(C)(C)O2)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]([C:6]1[N:7]=[C:2]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:33]=[CH:34][C:25]=2[CH2:24][N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:3]=[CH:4][CH:5]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reactant: O=Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1-c1cccc(C=O)n1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 24.3 g (84.8 mmol) of Na2CO3(H2O)10 in a mixture of 120 ml of methanol and 450 ml of water was added to a mixture of 6.30 g (33.9 mmol) of 6-bromopyridine-2-carbaldehyde, 15.6 g (33.9 mmol) of tert-butyl phenyl{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}carbamate and 1.96 g (1.70 mmol) of Pd(PPh3)4 in 600 ml of toluene by vigorous stirring at room temperature. The resulting mixture was stirred at 80° C. for 12 h. Thereafter, this mixture was cooled to room temperature, the organic layer was separated, dried over MgSO4, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=50:1 and then 10:1, vol.). Yield 9.50 g (64%). Anal. calc. for C28H26N2O3: C, 76.69; H, 5.98; N, 6.39. Found: C, 76.87; H, 6.12; N, 6.25. 1H NMR (CDCl3): 10.03 (s, 1H, CHO), 7.94-7.98 (m, 2H, 3,5-H in Py), 7.88 (m, 1H, 8-H in naphthyl), 7.83 (m, 1H, 4-H in Py), 7.75 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.45 (m, 1H, 7-H in naphthyl), 7.34 (m, 1H, 6-H in naphthyl), 7.11-7.18 (m, 4H, 5-H in naphthyl and 3,4,5-H in Ph), 7.03 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 6.93 (m, 2H, 2,6-H in Ph), 5.06 (d, J=15.9 Hz, 1H, CHH′N), 4.52 (d, J=15.9 Hz, 1H, CHH′N), 1.40 (s, 9H, tBu).
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:61]1[CH:66]=[C:65](B(O)O)[CH:64]=[N:63][CH:62]=1>>[CH3:33][S:30]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:11]4[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=4)=[C:2]([C:65]4[CH:66]=[N:61][CH:62]=[N:63][CH:64]=4)[C:3]3=[O:34])=[CH:8][CH:7]=2)[CH2:25][CH2:26]1)(=[O:31])=[O:32]
Reactant: OB(O)c1cncnc1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cncnc2)=C3c2ccc(C(F)(F)F)cc2)CC1
Yield: 14 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-6-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]-3-[4-(trifluoromethyl)phenyl]-1H-inden-1-one obtained in Step 1 of Example 47 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (14%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>C(Cl)Cl>[O:15]=[C:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([NH:2][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3cccnc3)cc2)CC1
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a stirred solution of 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) (8.76 g, 0.32 mol) in methylene chloride (100 mL) at room temperature was added triethylamine (9 mL). To this mixture was added a mixture of 3-pyridinesulfonyl chloride (7.45 g, 0.035 mol) and triethylamine (9 mL). The reaction was stirred for 18 hours. The reaction mixture was concentrated. The product was flash silica gel chromatographed eluting with 7:3 ethyl acetate/hexanes and then flash silica gel chromatographed eluting with 3% methanol in methylene chloride to give the titled compound as a yellow solid (1.34 g, 13%); 1H NMR (300 MHz, CDCl3) δ 2.54 (t, J=6 Hz, 4H), 3.56 (t, J=6 Hz, 4H), 6.79 (s, 1H), 6.85 (d, J=12 Hz, 2H), 6.98 (d, J=12 Hz, 2H), 7.40 (m, 1H), 7.97 (dd, J=3 Hz, 1H), 8.75 (dd, J=6 Hz, 1H), 8.90 (d, J=3 Hz, 1H); MS (ES) m/z: 331.9 (MH+, 100%); HRMS Calcd. for C16H17N3O3S(MH+): 332.1063. Found: 332.1063.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][C:21]1[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)cc1

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 4-methylbenzyl bromide (0.71 g; 3.85 mmol) and K2CO3 (1.5 g; 10.9 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (10 ml) and hydrochloric acid (6 N; 30 ml). Pure 5-amino-3,3-dimethyl-1-(4-methyl-benzyl)-6-nitro-1,3-dihydro-indol-2-one (1.18 g) precipitates by pouring the reaction mixture in ice-water.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]([O-:39])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[N:24][N:25]=1)(=[O:10])=[O:9].[Na+]>C(Cl)Cl.CCOCC>[S:8]([OH:39])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][N:25]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)[O-])s2)CC1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)s2)N1OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 25.7 %

Procedure:
TFA (0.20 mL) was added to a 0° C. mixture of sodium (2S,5R)-2-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-6-yl sulfate (50 mg, 0.10 mmol) in dry DCM (0.60 mL). The reaction mixture was stirred at 0° C. for 2-3 hrs and then diluted with ether (−10 mL). The precipitate was collected via centrifugation, washed with ether (3×) and dried under high vacuum to afford (2S,5R)-7-oxo-2-(5-(piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (10 mg, 25%) after prep-HPLC using ammonium formate buffer. ESI-MS (EI+, m/z): 390.12.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=[O:18])[CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C[Si](Cl)(C)C>CCCCO>[N:27]1([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=[O:18])[CH2:13][CH2:12]4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1.[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=[O:18])[CH2:13][CH2:12]4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: NC(=O)C1CCN(c2nc(Cl)nc3[nH]ccc23)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(C(N)=O)CC4)c4cc[nH]c4n3)cc2)CC1
Product: NC(=O)C1CCN(c2nc(Nc3ccc(N4CCNCC4)cc3)nc3[nH]ccc23)CC1

Procedure:
A mixture of 1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (80 mg, 0.28 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (125 mg, 0.57 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in n-BuOH (3 mL) was stirred at 130° C. for 20 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give 1-(2-(4-(piperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (4 mg) (MS 421.5 (M+H)) and 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (6 mg) (MS 463.5 (M+H); UV 200.0, 272.8 nm).